Effect Of Oxythiamine Research Articles

A dose- and time-dependent effect of oxythiamine on cell growth inhibition in non-small cell lung cancer

The high mortality rate of non-small-cell lung cancer (NSCLC) is mostly due to the high risk of recurrence. A comprehensive understanding of proliferation mechanisms of NSCLC would remarkably contribute to blocking up the invasion and metastasis of tumor cells. In our previous study, the remarkable decreased activity of Thiamine-dependent enzymes (TDEs), involving in intermediary metabolism responsible for energy production of tumor, was found under conditions of thiamine deficiency in vivo. To explore the effect of Oxythiamine (OT), a TDEs antimetabolite, on cell growth, we co-cultured A549 cells with OT in vitro at various doses (0.1, 1, 10 and 100 μM) and time periods (6, 12, 24 and 48 h) and subsequent cell proliferation and apoptosis assays were performed respectively. Our findings demonstrated that A549 cells proliferation was significantly downregulated by OT treatment in a progressively dose as well as time dependent manner. Inhibition of TDEs resulted in antagonism of lung cancer growth by inducing cells to cease the cycle as well as apoptotic cell death. We concluded a critical role of OT, a TDEs antagonistic compound, indicating the potential target of its practical use.

Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro

Oxythiamine (OT) and 3-deazathiamine (DAT) are the antimetabolites of thiamine. The aim of study was to compare the effects of OT and DAT pyrophosphates (-PP) on the kinetics of mammalian pyruvate dehydrogenase complex (PDHC) and the in vitro culture of HeLa cells. The kinetic study showed that 3-deazathiamine pyrophosphate (DATPP) was a much stronger competitive inhibitor (Ki = 0.0026 μM) of PDHC than OTPP (Ki = 0.025 μM). Both Ki values were much lower versus K m for thiamine pyrophosphate (0.06 μM). However, DATPP added to the culture medium for the HeLa cells culture did not hamper the rate of cell growth and showed not significant impact on the viability of the cells, whereas OTPP and OT showed a significant cytostatic effect. The differences between the thiamine antivitamins in their effect on cell growth in vitro may be due to differences in physicochemical properties and difficulty in DAT transport across the cell membrane.

The in vitro and in vivo anti-metastatic efficacy of oxythiamine and the possible mechanisms of action

This study examined the anti-metastatic effects of oxythiamine (OT) both in cell culture and in vivo. Cell culture results revealed that OT (0-20 microM) significantly inhibited the invasion and migration (IC(50) = 8.75 microM) of Lewis lung carcinoma (LLC) cells. These effects of OT were accompanied by the inhibition of metalloproteinases-2 and -9 (MMP-2, MMP-9), urokinase-type plasminogen activator (uPA) activities and by the increases in protein expression of tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1, TIMP-2). We then implanted (s.c.) C57BL/6 mice with LLC cells and supplemented the mice with a low- or a high-dose of OT (250 or 500 mg/kg BW) daily for 5 wk. During the 5-wk period, OT supplementation decreased plasma MMP-2 activity in a dose-dependent manner, and this effect was significant after 4 wk of tumor cell implantation. Tumor metastasis was found to confine to the lungs of mice injected with the tumor cells. High-OT supplementation strongly lowered the number and area of tumors and inhibited protein expression of MMP-2 and MMP-9 in the lungs. In addition, high-OT supplementation markedly decreased the extent of proliferating cell nuclear antigen (PCNA) staining in the lungs. By contrast, OT supplementation increased TIMP-1 and -2 protein expression in the lungs. These results demonstrate that OT supplementation attenuates tumor cell metastasis, possibly via inhibition of protein expression of MMPs, extent of PCNA staining and via increase of proteins expression of TIMPs.

Inhibition of Protein Phosphorylation in MIA Pancreatic Cancer Cells: Confluence of Metabolic and Signaling Pathways

Oxythiamine (OT), a transketolase inhibitor, is known to inhibit pancreatic cancer cell proliferation. In this study, we investigated the effect of inhibition of the transketolase pathway on signaling pathways in MIA PaCa cancer cells using in-house proteomic techniques. We hypothesized that OT alter protein phosphorylation thus affecting cell cycle arrest and cell proliferation. MIA PaCa-2 cells were cultured in media containing an algal (15)N amino acid mixture at 50% enrichment, with and without OT, to determine protein expression and synthesis. Analysis of cell lysates using two-dimensional gel electrophoresis matrix assisted laser desorption and ionization time-of-flight and time-of-flight mass spectrometry (2-DE-MALDI-TOF/TOF MS) identified 12 phosphor proteins that were significantly suppressed by OT treatment. Many of these proteins are involved in regulation of cycle activities and apoptosis. Among the proteins identified, expression of the phosphor heat shock protein 27 (Hsp27) was dramatically inhibited by OT treatment while the level of its total protein remained unchanged. Hsp27 expression and phosphorylation is known to be associated with drug resistance and cancer cell survival. The changes in phosphorylation of key proteins of cancer proliferation and survival suggest that protein phosphorylation is the confluence of the effects of OT on metabolic and signaling pathways.

Modification of thiamine pyrophosphate dependent enzyme activity by oxythiamine inSaccharomyces cerevisiaecells

Oxythiamine is an antivitamin derivative of thiamine that after phosphorylation to oxythiamine pyro phosphate can bind to the active centres of thiamine-dependent enzymes. In the present study, the effect of oxythiamine on the viability of Saccharomyces cerevisiae and the activity of thiamine pyrophosphate dependent enzymes in yeast cells has been investigated. We observed a decrease in pyruvate decarboxylase specific activity on both a control and an oxythiamine medium after the first 6 h of culture. The cytosolic enzymes transketolase and pyruvate decarboxylase decreased their specific activity in the presence of oxythiamine but only during the beginning of the cultivation. However, after 12 h of cultivation, oxythiamine-treated cells showed higher specific activity of cytosolic enzymes. More over, it was established by SDS-PAGE that the high specific activity of pyruvate decarboxylase was followed by an increase in the amount of the enzyme protein. In contrast, the mitochondrial enzymes, pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes, were inhibited by oxythiamine during the entire experiment. Our results suggest that the observed strong decrease in growth rate and viability of yeast on medium with oxythiamine may be due to stronger inhibition of mitochondrial pyruvate dehydrogenase than of cytosolic enzymes.

Phenytoin ameliorates the memory deficit induced in the young chick by ethanol toxicity in association with thiamine deficiency

The experiments reported in this series of studies demonstrate that thiamine deficiency, induced pharmacologically by oxythiamine (OT) coupled with the acute administration of ethanol can adversely affect memory processing in the young chick. The interaction between the avitaminosis and ethanol neurotoxicity exerted its effects through the inhibition of the development of the intermediate (ITM) stage of memory (i.e., following 10 min after training), consequently affecting development of the long-term stage of memory and leaving the short-term memory stage intact. The amnesic effect of OT-induced thiamine deficiency and exposure to alcohol was ameliorated by the administration of phenytoin [diphenylhydantoin (DPH)] immediately following the training experience. As the ITM stage of memory has been suggested to rely on the activities of Na +/K + ATPase, and as DPH is a facilitator of Na +/K + ATPase activity amongst its other actions, it may be that the combined effect of OT and ethanol exposure is by interfering with Na +/K + ATPase activity, thus undermining the expression and maintenance of the memory in the period from 10 min following aversant training.

A corticosteroid mechanism as the key stage in the thymotrophic effect of oxythiamine in rats

A corticosteroid mechanism as the key stage in the thymotrophic effect of oxythiamine in rats

Effect of oxythiamine and pyrithiamine on thiamine levels in the blood, liver and urine of rats (author's transl)

Thiamine (T) deficient state and various functional and morphological changes in rat liver were induced, after several days, with T antagonists, oxythiamine (OT) or pyrithiamine (PT), and a thiamine deficient diet (TDD). The relationship between the extent of liver damage and T levels in blood, liver and urine were studied in OT treated rats fed a TDD (OTD group). PT treated rats fed a TDD (PTD group), OT treated rats (OT group), PT treated rats (PT group) and rats fed a TDD (TDD group). The T levels in blood and liver of OT group, PT group, OTD group, PTD group and TDD group were 89% and 91%, 76% and 88%, 25% and 14%, 33% and 16%, 24% and 15% compared with the data in the control group, respectively. Effects of OT or PT on T levels were not remarkable in some cases, and such may be due to the duration time of T antagonists, which was considered to be 3-15 hours in PT treated rats, and 0-18 hours in PT treated rats, as assessed by urinary T measurements. Treatment of T antagonist twice daily is recommended to obtain a definite T deficient state. Our results suggest that the extent of liver damage is related to the T levels in tissue.

The Effect of Oxythiamine on Rat Ovoimplantation

The Effect of Oxythiamine on Rat Ovoimplantation

Effect of antivitamins on the microbiological biosynthesis of vitamines. IV. Effect of oxythiamine on the thiamine phosphorylation by the thiamine pyrophosphokinase of yeast

Effect of antivitamins on the microbiological biosynthesis of vitamines. IV. Effect of oxythiamine on the thiamine phosphorylation by the thiamine pyrophosphokinase of yeast

Effects of oxythiamine and neopyrithiamine on phosphorylation of thiamine by thiamine phosphorylase from rat intestine

Effects of oxythiamine and neopyrithiamine on phosphorylation of thiamine by thiamine phosphorylase from rat intestine

Effect of oxythiamine on the growth of chicks.

Effect of oxythiamine on the growth of chicks.

EFFECT OF OXYTHIAMINE ON BLOOD PYRUVATE-LACTATE RELATIONSHIPS AND THE EXCRETION OF THIAMINE IN RATS

EFFECT OF OXYTHIAMINE ON BLOOD PYRUVATE-LACTATE RELATIONSHIPS AND THE EXCRETION OF THIAMINE IN RATS